The hemagglutinin of the 2009 pandemic H1N1 influenza virus is a derivative of and is antigenically related to classical swine but not to seasonal human H1N1 viruses. We compared the A/California/7/2009 (CA/7/09) virus recommended by the WHO as the reference virus for vaccine development, with two classical swine influenza viruses A/swine/Iowa/31 (sw/IA/31) and A/New Jersey/8/1976 (NJ/76) to establish the extent of immunologic cross-reactivity and cross-protection in animal models. Primary infection with 2009 pandemic or NJ/76 viruses elicited antibodies against the CA/7/09 virus and provided complete protection from challenge with this virus in ferrets;the response in mice was variable and conferred partial protection. Although ferrets infected with sw/IA/31 virus developed low titers of cross-neutralizing antibody, they were protected from pulmonary replication of the CA/7/09 virus. The data suggest that prior exposure to antigenically related H1N1 viruses of swine-origin, by prior infection or receipt of the swine flu vaccine of 1976, provide some protective immunity against the 2009 swine-origin H1N1 virus. There are several potential strategies for the development of vaccines to protect humans against influenza viruses, including formalin inactivated whole or split virus, HA subunit, and live attenuated virus vaccines. Live attenuated influenza vaccines (LAIV) have several attributes related to safety, immunogenicity, cross-protection against antigenic drift strains, high yield and needle-free administration that make them attractive candidates for control of pandemic influenza. Live attenuated vaccines generally induce broadly cross-reactive protection, which may be a useful feature in the event of a pandemic if a vaccine generated from the actual pandemic strain is not available. LID scientists collaborated with scientists from MedImmune under a CRADA to evaluate candidate vaccines against pandemic influenza viruses, including the 2009 pandemic H1N1 virus. The vaccine virus generated by MedImmune contains the hemagglutinin (HA) and neuraminidase (NA) genes of the 2009 H1N1 pandemic influenza virus and the attenuating genes from the A/Ann Arbor/6/60 cold adapted (A/AA/6/60 ca) donor virus. The role of seasonal influenza vaccination in pandemic H1N1 disease was important to address because a large segment of the population is vaccinated annually. We administered one or two doses of a live attenuated pandemic H1N1 vaccine (p-LAIV), a seasonal trivalent inactivated (s-TIV) or seasonal live attenuated influenza vaccine (s-LAIV) to mice and ferrets and subsequently challenged them with a pandemic H1N1 virus. In both species, the p-LAIV vaccine was immunogenic and conferred complete protection against challenge. s-TIV did not confer protection in either animal model and s-LAIV did not confer any protection in ferrets. In mice, two doses of s-LAIV led to complete protection in the upper respiratory tract and partial protection in the lungs. Our data indicate that vaccination with the seasonal influenza vaccines did not confer complete protection in the lower respiratory tract in either animal model while the p-LAIV vaccine conferred complete protection in both animal models. Our observations also indicate that exposure to seasonal influenza vaccines may play a role in reducing susceptibility and morbidity from pandemic 2009 H1N1 infection and suggest the importance of exploring the underlying mechanisms of this phenomenon. The factors underlying the epidemiology of the 2009 H1N1 influenza pandemic were undefined. Although the virus is genetically and antigenically distinct from seasonal human H1N1 viruses, the clinical data from the pandemic suggested that prior exposure to influenza played a significant role in susceptibility to disease and immune response to the pandemic virus. Individuals over 50 years of age had antibodies that cross-reacted with and appeared to be less susceptible to infection with the pandemic H1N1 (p-H1N1) virus, presumably due to prior exposure to an antigenically related H1N1 influenza virus. In addition, data from p-H1N1 vaccine trials suggested that a large segment of the population had been exposed to an influenza virus that "primed" individuals such that only one dose of the novel pandemic vaccine was sufficient to elicit a protective antibody titer. This observation was unexpected because studies conducted in the 1970s had shown that 2 doses of vaccine were needed to immunize a nave population. We evaluated the effect of seasonal (s) H1N1 infection, s- trivalent inactivated vaccine (s-TIV) and s- trivalent live attenuated influenza vaccine (s-LAIV) prior to immunization with a pandemic live attenuated vaccine (p-LAIV) in mice. We compared serum and mucosal antibody, pulmonary CD8 and CD4 responses and the virologic response to challenge with a wild-type 2009 pandemic H1N1 (p-H1N1) virus. Two doses of p-LAIV induced cellular immune and robust ELISA and neutralizing antibody responses that were associated with complete protection from p-H1N1 challenge. A single dose of p-LAIV induced a cellular response and ELISA but not neutralizing antibody response and incomplete protection from p-H1N1 virus challenge. Primary infection with s-H1N1 influenza virus followed by a dose of p-LAIV resulted in cross-reactive ELISA antibodies and a robust cellular immune response that was also associated with complete protection from p-H1N1 virus challenge. A lower magnitude but similar response associated with partial protection was seen in mice that received a dose of s-LAIV vaccine followed by p-LAIV. Mice that received a dose of s-TIV followed by p-LAIV did not show any evidence of priming. In summary, prior infection with a seasonal influenza virus or s-LAIV primed mice for a robust response to a single dose of p-LAIV that was associated with protection equivalent to two doses of the matched pandemic vaccine.